It has been proposed that the antiestrogen tamoxifen induces liver tumors in rats and genotoxic effects in vitro through metabolic activation involving, initially, α-hydroxylation of the ethyl group. To test this hypothesis, the extent of DNA adduct formation in primary rat hepatocytes treated with tamoxifen and α-hydroxytamoxifen was investigated. Hepatocytes from female Fischer F-344 rats were treated with 1 or 10 µm concentrations of either α-hydroxytamoxifen or tamoxifen. DNA was isolated and analyzed for the presence of DNA adducts by 32P postlabeling. Chromatography on polyethyleneimine cellulose thin layer chromatography and reverse-phase high performance liquid chromatography revealed that the same pattern of adducts was formed by both compounds. However, the level of adduct formation was 25 and 49 times greater with α-hydroxytamoxifen than with tamoxifen at 1 and 10 µm, respectively. The formation of α-hydroxytamoxifen as a metabolite of tamoxifen was demonstrated by mass spectrometric analysis of the extracted culture medium. α-Hydroxytamoxifen was found to react with DNA in the absence of metabolizing enzymes. These results demonstrate the involvement of α-hydroxylation in the metabolic activation of tamoxifen.

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Supported by the Cancer Research Campaign.

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